Bile acids are involved in a variety of physiological and pathological processes of the liver and biliary system. For the past several years, I have studies intrahepatic cholestasis and hepatocellular injuries induced by lithocholic or chenodeoxycholic acid, as well as the influence of cholic acid on these pathological processes in rats, hamsters and isolated, perfused rat livers. I wish to continue and extend my studies with particular reference to the following problems: 1) identification and characterization of the primary subcellular changes in cholestasis induced by bile acids or by several other cholestatic agents; 2) the relationship between bile canalicular structure and function (e.g. structural distortion of the membrane and fluid transport, functional significance of the membrane-associated enzymes, etc.); 3) the factors which influence the hepatotoxicity of bile acids (e.g. their dose, mode of administration, bile acid pool and bacterial conversion in the intestine); and 4) the hepatic uptake, transport and secretion of bile acids in relation to the hepatic pathophysiology. The above problems will be studied in acute experiments in which rats or other species with or without a bile fistula are used. Bile acids or other agents will be administered intravenously either singly or in combination. Part of problem 3 will be studied using chronic experiments in which bile acids are administered orally. Experimental changes will be assessed by a combination of some of the following methods: a) light microscopy, transmission electron microscopy (including the freeze-fracture replica technique), scanning electron microscopy (secondary, backscatter and transmission modes); b) enzyme histochemistry; c) autoradiography; d) blood chemistry, e.g., serum transaminases, alkaline phosphatase, etc.; e) analysis of bile acids in the bile, feces, and tissue. Particular emphasis will be placed on the correlation between the alterations in the subcellular structure and their functions.